title: Very-high-dose alpha-tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke-prone spontaneously hypertensive rats.
abstract: Tocopherols and tocotrienols constitute the vitamin E family. Although alpha-tocotrienol is the most neuroprotective form of vitamin E proved to be effective against stroke, alpha-tocopherol is the most abundant in nature and is used most often for disease prevention/treatment. A recent metaanalysis of human studies suggested that alpha-tocopherol supplementation increases all-cause mortality. Therefore, we investigated the effects of alpha-tocopherol ( approximately 44 mg/kg body weight; equivalent to 2,600 mg/human/day) on the central nervous system (CNS) of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP treated with high dose alpha-tocopherol had significantly higher blood pressure than untreated controls fed a basal diet that contained approximately 4 mg tocopherols/kg body weight, but neither group experienced a change in degree of lipid peroxidation in serum or CNS tissue. Biochemical/immunohistochemical analyses demonstrated that expressions of phosphorylated neurofilament H protein, glial fibrillary acidic protein and cathepsin D in the CNS tissue were significantly enhanced in alpha-tocopherol-supplemented rats, whereas expressions of SOD2 and Bcl-xL were diminished in response to alpha-tocopherol supplementation. Similarly, the frequency of cathepsin D-positive cells, corresponding mostly to microglial cells, was significantly increased in alpha-tocopherol-supplemented rats. Alpha-tocopherol supplementation also increased the number of lysosomes and lipofuscin granules in perikarya of both hippocampal pyramidal and Purkinje cells. Furthermore, alpha-tocopherol supplementation increased the frequency of glial filaments and lipofuscin granules in astrocytes and lysosomes in microglial cells that were frequently occupied with phagocytosed inclusion structures. The present results are the first to suggest that a very high dose of alpha-tocopherol supplementation increases blood pressure in SHRSP rats and influences the CNS tissue in a manner that seems adverse.
authors.affiliation: Laboratory of Cell Biology, College of Nutrition, Koshien University, Takarazuka, Hyogo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Motoko
authors.initials: M
authors.lastname: Shiozaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibata
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Gotow
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002402:Cathepsin D / Q000187:drug effects / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000209:etiology; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission; D016900:Neurofilament Proteins / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020521:Stroke / Q000235:genetics; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000009:adverse effects*; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D002402:Cathepsin D; D005904:Glial Fibrillary Acidic Protein; D016900:Neurofilament Proteins; D013482:Superoxide Dismutase; D024502:alpha-Tocopherol; D051020:bcl-X Protein; D000099156:Superoxide Dismutase 2; C051774:neurofilament protein H